Circadian rhythms regulate human behavior and physiology within the 24 hour day to optimize processes, from gene expression to cognition. Dysregulation of those rhythms are associated with sleep disorders, cognitive and physical performance, cancer, and chronic metabolic and neurologic disease. Despite the importance of circadian rhythms to human health and their fundamental role demonstrated in model organisms, little is known about the biological connection between human circadian rhythms and our health and physiology. We propose to identify novel genetic factors involved in circadian rhythms by sequencing extreme circadian rhythm disorder patients from clinical cohorts (n~200). Advanced Sleep Phase Syndrome (ASPS) and Delayed Sleep Phase Syndrome (DSPS) are inherited neurological sleep disorders of the circadian clock, which present as extremely shifted sleep timing. Familial studies identified mutations in genes encoding molecular components of the circadian clock (PER2, PER3) or regulating the speed/pace of the clock (CSNK1D), causing extreme advance or delay in sleep onset. We hypothesize that ASPS and DSPS subjects harbor rare loss-of-function mutations in components of the circadian clock, including input/output pathways and the core molecular clock. This hypothesis will be tested in 2 specific aims: Aim 1 will identify genetic variants robustly associated with Advanced and Delayed Sleep Phase Syndrome in clinical cohorts. I will learn phenotyping of circadian disorders and exome sequencing and analysis. Aim 2 will determine the mechanisms underlying the disease process by determining the function of ASPS and DSPS genetic mutations on cellular circadian rhythms and screening for novel therapeutic compounds. Through Aim 2 I will develop skills in circadian cell culture assays and associated analysis techniques, as well as learn compound screening. The results of this study will identify new causal genetic factors for ASPS and DSPS. Through these results we will elucidate novel genes and pathways underlying circadian regulation. These findings will open potential new avenues of therapeutics for rare circadian rhythms disorders, increase our understanding of the basic mechanisms of circadian biology, and open new avenues for treatment of more common circadian rhythm associated chronic diseases. To achieve my long-term career goal to be one of the leading human geneticists in the field of chronobiology, I will expand my current expertise in genome-wide studies of common variation in complex traits into circadian clinical sample phenotyping and exome sequencing identification of causal rare variants to achieve my career goal. The research proposed in this K01 will serve as an essential stepping stone to acquire this training.